Dose of Lacosamide

Dosing: Adult (Uptodate)

Partial onset seizure:

Monotherapy: Oral, IV:

Initial: 100 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability.

Alternative initial dosage: Loading dose: 200 mg followed approximately 12 hours later by 100 mg twice daily for 1 week; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Note: Administer loading doses under medical supervision because of the increased incidence of CNS adverse reactions.

Maintenance: 150 to 200 mg twice daily. Note: For patients already on a single antiepileptic and converting to lacosamide monotherapy, maintain the maintenance dose for 3 days before beginning withdrawal of the concomitant antiepileptic drug. Gradually taper the concomitant antiepileptic drug over ≥6 weeks.

Adjunctive therapy: Oral, IV:

Initial: 50 mg twice daily; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability.

Alternative initial dosage: Loading dose of 200 mg followed approximately 12 hours later by 100 mg twice daily for 1 week; may be increased at weekly intervals by 50 mg twice daily based on response and tolerability. Note: Administer loading doses under medical supervision because of the increased incidence of CNS adverse reactions.

Maintenance dose: 100 to 200 mg twice daily (maximum: 400 mg daily)

Status epilepticus, refractory (off-label use): IV: 200 to 400 mg followed by a daily maintenance dose of 200 to 600 mg daily in 2 divided doses (Albers, 2011; Goodwin, 2011; Kellinghaus, 2011; NCS [Brophy, 2012]). Note: Although the Neurocritical Care Society recommends administration of the initial dose at a rate of 200 mg over 15 minutes, others have administered doses of up to 400 mg IV push over ≤5 minutes without apparent harm (Goodwin, 2011; Kellinghaus, 2011; NCS [Brophy, 2012]).

How do seizures stop? A review

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738747/

This is an interesting article from Fred Lado and Solomon Moshe, which reviews literature on mechanisms for seizure termination.

How does a status epilepticus become super refractory?

http://brain.oxfordjournals.org/content/134/10/2802

This question is obviously crucial to successful management. It is a common clinical experience that the more severe the precipitating insult (for instance, in status epilepticus after trauma infection or stroke), the more likely is the status epilepticus to become super-refractory. However, super-refractory status epilepticus also occurs frequently in previously healthy patients without obvious cause.

In all these cases, the processes that normally terminate seizures have proved insufficient (for review, see Lado and Moshe, 2008). At a cellular level, one of the most interesting recent discoveries has been the recognition that receptors on the surface of axons are in a highly dynamic state, moving onto (externalization), away from (internalization) and along the axonal membrane. This ‘receptor trafficking’ intensifies during status epilepticus, and the overall effect is a reduction in the number of functional γ-aminobutyric acid (GABA) receptors in the cells affected in the seizure discharge (Arancibia and Kittler, 2009; Smith and Kittler, 2010). As GABA is the principle inhibitory transmitter, this reduction in GABAergic activity may be an important reason for seizures to become persistent. Furthermore, the number of glutaminergic receptors at the cell surface increases, and the reduction in the density of the GABA receptors is itself triggered it seems by activation of the glutaminergic receptor systems. Why this should happen is unknown, and from the epilepsy point of view is certainly maladaptive. This loss of GABAergic receptor density is also the likely reason for the increasing ineffectiveness of GABAergic drugs (such as benzodiazepines or barbiturates) in controlling seizures as the status epilepticus becomes prolonged (Macdonald and Kapur, 1999). It has also been repeatedly shown that the extracellular ionic environment, which can change in status epilepticus, may be an important factor in perpetuating seizures, and the normally inhibitory GABA(A)-mediated currents may become excitatory with changes in extracellular chloride concentrations (Lamsa and Taira, 2003).

Other cellular events might also be important. Mitochondrial failure or insufficiency may be one reason for the failure of seizure termination and cellular damage and mitochondrial processes are involved in cell necrosis and apoptosis (Cock et al., 2002). Another category of disease triggering persistent status epilepticus is inflammatory disease (Tan et al., 2010), and inflammatory processes may be important in the persistence of status epilepticus. The opening of the blood–brain barrier almost certainly plays a major role in the perpetuation of seizures, due to a variety of possible mechanisms (Friedman and Dingledine, 2011), and this may be especially the case in status epilepticus due to inflammation (Marchi et al., 2011). This may explain the benefits of steroids in the therapy of status epilepticus. Leakage of the blood–brain barrier will also lead to higher potassium levels and excitation (David et al., 2009). No genetic mechanism has been identified to explain the failure of seizure termination although massive changes in gene expression occur within minutes of the onset of status epilepticus.

At a systems level, it has been suggested rather fascinatingly and counter intuitively that status epilepticus results from a failure to synchronize seizure activity (Schindler et al., 2007a, b; Walker, 2011), and that the lack of synchrony somehow prevents seizure termination.

These mechanisms influence strategies for therapy. However, often overriding is the importance of establishing cause of the status epilepticus, for emergency therapy directed at the cause may be crucial in terminating the episode (for review of the influence of aetiology on prognosis, see Neligan and Shorvon, 2011).

Spinal cord section